Methods for delivering regional citrate anticoagulation (rca) during extracorporeal blood treatments

ABSTRACT

Disclosed are methods, compositions, and devices for improved delivery of regional citrate anticoagulation during extracorporeal blood treatments. Methods comprise quantification of the clearance of calcium and/or citrate using one or more on-line/in-line sensors, establishing a correlation between the differential conductivity between afferent and efferent dialysate and the clearance of calcium and/or citrate. The methods described herein further include quantifying citrate clearance using glucose as a surrogate.

RELATED APPLICATIONS

This application is an international application that claims the benefitof priority to U.S. Provisional Patent Application Nos. 62/151,934,filed Apr. 23, 2015 and 62/210,363, filed Aug. 26, 2015, the disclosuresof which are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The present disclosure relates generally to systems and methods for theprevention of blood clotting during extracorporeal blood circulationtherapies. More particularly, the present disclosure relates to systemsand methods for delivering regional citrate anticoagulation (RCA) duringextracorporeal blood treatments.

Description of the Related Art

Although regional citrate anticoagulation (RCA) has been used fordecades in many extracorporeal blood circulation therapies and is wellknown for the prevention of clotting in extracorporeal circuitscontaining blood treatment devices for 24 hours and longer, itsimplementation is complex and fraught with complicated formulation ofcustom dialysates. Furthermore, the delivery of RCA requires frequentmonitoring of the patient's electrolyte and acid/base status. A varietyof different protocols have been developed and promoted by variousinvestigators but, to date, no standardization around a single protocolhas evolved. Thus, RCA delivery continues to be a highlymanually-intensive and monitoring-intensive anticoagulation technique.Furthermore, no instrumentation has ever been developed or submitted tothe FDA that purports to control and automate the process so as toreduce to a minimum, the required degree of human intervention andincrease to a maximum, the safety inherent in using such a system.

Fundamentally, RCA is accomplished by infusing a citrate-containingsolution into the arterial limb of an extracorporeal circuit as close aspossible to the blood access device to insure anticoagulation of thelargest possible length of the circuit. The addition of trivalentcitrate anions has the effect of chelating both ionized calcium andmagnesium divalent cations. By infusing sufficient citrate to reduce theionized calcium concentration to below 0.35 mmol/L in the incomingblood, coagulation, which is dependent on ionized calcium, is prevented.In some extracorporeal procedures such as blood collection/cellseparation, the citrate/calcium complexes are simply returned to thedonor.

Allowing the calcium-citrate complexes to return to a healthy patientduring a 1-2 hour blood donation event does not elicit any clinicalsequelae because it is easily metabolized to bicarbonate and CO₂ by themitochondria of the liver, muscle and skeletal tissue. However,returning the citrate/calcium to a patient undergoing continuous renalreplacement therapy (CRRT) for acute kidney failure or one who istrending towards sepsis with a possible hyporesponsive liver must beprevented. Otherwise, the patients can develop citrate toxicity, hyperor hypocalcemia, acid/base derangements, and a host of other sequelaesuch as arrhythmias which can be fatal.

Currently, this is typically avoided by allowing the calcium/citratecomplexes to diffuse through a dialyzer or hemofilter membrane which isbeing perfused by dialysate or by extracting them convectively withcopious amounts of ultrafiltration in straight hemofiltration proceduresor both in the case of hemodiafiltration. When using these procedures,the calcium lost to the effluent must be replaced into the patient'sblood in order to avoid hypocalcemia. This is typically accomplished byinfusing a solution of calcium chloride or calcium gluconate into thevenous return limb of the extracorporeal circuit, again, as close to theblood access connection as possible so as to bring the patient's ionizedcalcium concentration back into the 0.9-1.3 mmol/L physiologic range.

SUMMARY OF THE INVENTION

One of the principal factors contributing to the difficulty in providingcitrate anticoagulation is the fact that determining the correct rate atwhich to infuse calcium into the venous blood line is dependent onknowing how much citrate/calcium has been cleared from the circuit.This, in turn, is dependent on the blood flow rate, the dialysate flowrate, the ultrafiltration rate, and the surface area of availablemembrane in the dialyzer/hemofilter; all of which can changeintra-treatment. It is also important to know the amount of citratebeing removed from the circuit because this translates into theremaining quantity being delivered to the patient, which must becompensated for by adjusting the amount of bicarbonate in the dialysateor replacement fluid in order to keep the patient in a correct acid/basebalance.

The impediment to automating this process to this point has been theabsence of knowledge of the exact amount of calcium and citrate beingcleared from the circuit. In order to pass regulatory safety muster, onemust be able to assure at any point in time that the composition ofblood returning to the patient is nearly identical to that which camefrom the patient (within reasonable clinical margins). Since theperformance of a dialyzer/hemofilter cannot be assured to remainconstant over the course of a 24-hour or longer treatment, being able toquantify the citrate and/or calcium being transported through themembrane and into the effluent dialysate becomes mandatory if theobjective is to claim automation and safety.

Automating and standardizing this process could be accomplished with thedevelopment of on-line/in-line sensors, preferably located in theeffluent dialysate circuit, which would allow the quantification of theclearance of calcium and citrate. Accordingly, in one embodimentdescribed herein is a method for establishing a correlation between thedifferential conductivity between afferent and efferent dialysate andthe clearance of both calcium and citrate.

One of the options for a citrate infusate is tri-sodium citrate. Oncecitrate from this solution chelates calcium or magnesium in the blood towhich it is infused, sodium ions are liberated. These sodium ions willbe cleared at a rapid rate when a diffusive modality such as dialysis orhemodiafiltration is employed, which will increase the conductivity ofthe dialysate into which it is dispersed. It is reasonable to expectthat this conductivity could be sensed as it enters the effluentdialysate upon passage through the dialyzer/hemofilter membrane andcould, in turn, be correlated with the actual citrate/calcium clearanceseparately measured during development by a gold standard instrument. Ifthe correlation is repeatable over a range of flow rates and dialysatecompositions, the conductivity differential could then be used as anaccurate surrogate of citrate and/or calcium clearance. Further accuracycan be accomplished if both afferent and efferent dialysate streams werepassed through the same conductivity sensor thereby eliminating anyvariations between two independent sensors.

In some embodiments, systems and methods are provided which allows forregional citrate anticoagulation in an extracorporeal circuitry, whereinthe system comprises an extracorporeal circuitry comprising a dialysatecircuit passing through a hemofilter, one or more sensors for detectingthe differential conductivity between afferent and efferent dialysate,and automation hardware and software that calculates the clearance ofcalcium and citrate and automates the reinfusion of ionized calcium intothe venous return leg of the extracorporeal blood path closest to thepatient. In some embodiments, the method further comprises infusing theblood with citrate into the arterial limb of an extracorporeal circuitas close as possible to the blood access to reduce the ionized calciumconcentration, and returning the blood to the subject with physiologicallevels of calcium. In some embodiments, the citrate is tri-sodiumcitrate, wherein citrate chelates calcium, thereby forming acalcium/citrate complex. In some embodiments, the level of ionizedcalcium is decreased to less than 0.35 mmol/L but, in some embodiments,the level of ionized calcium is greater than zero. In some embodiments,calcium is infused back into the blood just prior to returning the bloodto the subject, wherein the concentration of the ionized calcium isrestored to physiological levels of 0.9-1.3 mmol/L (e.g., 0.9, 1.0, 1.1,1.2, or 1.3 mmol/L or within a range defined by any two of theaforementioned concentrations).

In some embodiments, a method is provided which allows for regionalcitrate anticoagulation, wherein the method comprises introducing bloodinto an extracorporeal system comprising a blood path and a dialysatepath on opposite sides of a semipermeable membrane contained in ahemofilter, an affinity cartridge, and a fluorometer. In someembodiments, the affinity cartridge comprises a lectin (e.g.,Concanavalin A, Galanthus nivalis lectin (GNA), Lens culinaris (LCH),Ricinus communis Agglutinin (RCA), Arachis hypogaea (PNA), Artocarpusintegrifolia (AIL), Vicia villosa (VVL), Triticum vulgaris (WGA),Sambucus nigra (SNA), Maackia amurensis (MAL), Maackia amurensis (MAH),Ulex europaeus (UEH), or Aleuria aurantia (AAL) or any combination oflectins thereof). In some embodiments, a fluorescently labeled dextranis bound to the lectin. In some embodiments, the fluorescently labeleddextran is labeled with fluorescein isothiocyanate (FITC). In someembodiments, the method comprises diffusing glucose from the blood intothe effluent dialysate flow path during blood recirculation. In someembodiments, the glucose passes through the lectin affinity cartridgebinding to the lectin contained therein and displacing the fluorescentlylabeled dextran, whose concentration and rate of displacement isquantified by a downstream fluorometer and correlated to the clearancerate of glucose from blood which, in turn, is correlated to theclearance rate of citrate and calcium from blood. In some embodiments,the quantity of glucose levels is used in a feedback loop to determinethe infusion rate of calcium into the venous blood path.

In some embodiments, a method for providing regional citrateanticoagulation is provided, wherein the method comprises introducingblood into an extracorporeal system comprising a selective cytophereticdevice (SCD), an anion exchange cartridge, a hemofilter, and one or moresensors. In some embodiments, citrate is introduced into the system, andchelates calcium, forming a calcium/citrate complex. When blood ordialysate containing these calcium/citrate complexes pass over certainanion exchange resins, the citrate will be preferentially bound to theresin and exchanged for chloride ions. This has the effect of liberatingthe calcium ions that were previously bound to the citrate resulting inthe composition of the solution exiting the anion exchange cartridgebeing mostly devoid of calcium citrate and instead, mostly populated bycalcium chloride. In some embodiments, the method comprises returningthe calcium that was previously extracted from the blood by citratechelation to the patient by liberating it from the citrate via itspassage over an anion exchange resin after it has passed through thebulk of the extracorporeal circuit including any blood treatment devicescontained therein.

BRIEF DESCRIPTION OF THE DRAWINGS

In addition to the features described above, additional features andvariations will be readily apparent from the following descriptions ofthe drawings and exemplary embodiments. It is to be understood thatthese drawings depict typical embodiments, and are not intended to belimiting in scope.

FIG. 1 is a schematic diagram of one embodiment of a method for citrateclearance determination, wherein both afferent and efferent dialysatestreams are passed through the same conductivity sensor therebyeliminating any variations between two independent sensors.

FIG. 2 is a schematic diagram of one embodiment of the method forcitrate clearance determination, depicting the use of glucose as asurrogate for citrate. The glucose diffuses from the blood of a patientthrough the semipermeable membrane of a hemofilter into the effluentdialysate flow path and is introduced to an affinity cartridge having alectin bound thereto. Fluorescently labeled dextran is bound to thelectin. Fluorescently labeled dextran is displaced by the glucose, andthe concentration of displaced labeled dextran is detected andquantified. A high degree of correlation between the displacement ofglucose and the clearance of citrate and calcium allows the fluorometerreading to be translated into calcium and citrate clearance values.These values are then used in a feedback loop to set the infusion rateof calcium into the venous blood such that the ionized calciumconcentration of the returning blood is at or close to the prescribedvalue.

FIG. 3 is a schematic diagram of one embodiment of a method of providingRCA when a selective cytopheretic device (SCD) and a downstreamhemofilter are located in the blood path and the dialysate isrecirculated through both devices and an anion exchange cartridge from asingle reservoir. This embodiment illustrates how the dialysate,containing a large majority of calcium/citrate complexes that havediffused into it from the blood during its transit through thehemofilter can be recirculated through an anion exchange cartridge wherethe citrate is bound and exchanged for chloride thereby liberating thecalcium ions previously removed from the patient's blood and directingthis calcium chloride-containing dialysate back through the hemofilterwhere the calcium will diffuse back into the calcium-poor blood justprior to returning to the patient.

FIG. 4 is a schematic diagram of an embodiment similar to that depictedin FIG. 3 except that the dialysate is sent from a reservoir to a drainin a single pass format rather than recirculating it.

FIG. 5 is a schematic diagram of one embodiment wherein citrate captureand calcium release/reinfusion is implemented using an anion exchangecartridge in conventional modes of intermittent or continuous renalreplacement therapy where no SCD in employed.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Although the invention is described in various exemplary embodiments andimplementations as provided herein, it should be understood that thevarious features, aspects, and functionality described in one or more ofthe individual embodiments are not limited in their applicability to theparticular embodiment with which they are described. Instead, they canbe applied alone or in various combinations to one or more of the otherembodiments of the invention, whether the embodiments are described orwhether the features are presented as being a part of the describedembodiment. The breadth and scope of the present invention should not belimited by any exemplary embodiments described or shown herein.

As used herein, the term “glucose exchange medium” refers to a mediumwhich includes, but is not limited to, a resin, a bead, a column, acartridge, a porous membrane, or other medium through which a solutioncan pass, and which binds to or is capable of binding to glucose.

In some embodiments a method is provided for delivering regional citrateanticoagulation to a subject, as depicted in FIG. 1. In this embodiment,the method comprises introducing blood into an extracorporeal systemcomprising a hemofilter, infusing the blood with citrate to formcomplexes of citrate/calcium to prevent blood from coagulating in thehemofilter and the blood circuit, flowing the blood through thehemofilter, flowing dialysate through the hemofilter in a flow directionopposite of the blood flow, measuring the conductivity of the dialysateprior to passage through the hemofilter and measuring the conductivityof the dialysate after passage through the hemofilter to determine adifferential conductivity, infusing blood that has passed through thehemofilter with calcium chloride based on the measured differentialconductivity, and returning the blood to the subject. In someembodiments the method comprises monitoring the differentialconductivity between the afferent and the efferent streams of dialysate,determining an actual clearance of calcium and of citrate through themembrane, and correlating the differential conductivity to the actualclearance of calcium and citrate. In some embodiments, the citrate isinfused into the blood immediately upon entering the extracorporealsystem in order to ensure that the blood does not coagulate. In someembodiments, the flow rate of the blood through the extracorporealsystem is about 200 mL/min. One of skill in the art would recognize thatthe flow rates may be adjusted based on the specific application,capabilities, or needs of the method. In some embodiments, the flow rateof the dialysate is at least twice that of the flow rate of the blood,for example, at least 400 mL/min.

In some embodiments a method is provided for quantifying citrateclearance in an extracorporeal system using glucose as a surrogate, asdepicted in FIG. 2. This approach takes advantage of the fact thatglucose and citrate are nearly identical in molecular weight andtherefore their transport through a dialysis membrane is very similar.In this case, the preferred citrate infusate would be that which is mostcommonly used in RCA: anticoagulant citrate-dextrose-acid or ACD-A as itis commonly known. This solution contains 124 mmol/L of glucose. In someembodiments, the extracorporeal system comprises a lectin affinitycartridge, preferably a lectin affinity cartridge comprisingConcanavalin A, which is a lectin that has been well characterized as astrong binder of both monomeric glucose and the glucose polymer,Dextran. In some embodiments, however, the lectin affinity cartridgecomprises at least one or more of the following lectins Concanavalin A,Galanthus nivalis lectin (GNA), Lens culinaris (LCH), Ricinus communisAgglutinin (RCA), Arachis hypogaea (PNA), Artocarpus integrifolia (AIL),Vicia villosa (VVL), Triticum vulgaris (WGA), Sambucus nigra (SNA),Maackia amurensis (MAL), Maackia amurensis (MAH), Ulex europaeus (UEH),or Aleuria aurantia (AAL) or any combination of lectins thereof). Thatis, in some embodiments, in addition to Concanavilin A, the lectincartridge may contain one or more additional lectins so as to utilize amixed lectin bed (e.g., one or more lectins selected from the groupconsisting of Galanthus nivalis lectin (GNA), Lens culinaris (LCH),Ricinus communis Agglutinin (RCA), Arachis hypogaea (PNA), Artocarpusintegrifolia (AIL), Vicia villosa (VVL), Triticum vulgaris (WGA),Sambucus nigra (SNA), Maackia amurensis (MAL), Maackia amurensis (MAH),Ulex europaeus (UEH), and Aleuria aurantia (AAL) or any combination oflectins thereof).

In one embodiment, Concanavalin A (Con A), which has previously hadDextran that is labeled with the fluorescent marker FITC bound to it, issequestered in a flow-through container, which is located in theeffluent dialysate flow path. When a glucose-containing solution ispassed over this Con A-FITC-Dextran compound, the FITC-Dextran isdisplaced by the glucose and the intensity of the resultant fluorescencein the effluent fluid can be quantified fluorometrically and correlatedto the concentration of glucose in the perfused fluid. Although thistechnology has been attempted for use in blood glucose sensingparticularly for monitoring blood sugar levels in diabetes, it has neverbeen proposed or suggested for use in an extracorporeal bloodpurification modality. Its application in blood has been problematic dueto the fact that Con A is toxic if allowed to be released into apatient's bloodstream. In the proposed application, such a danger isnon-existent since the Con A will only be deployed in the effluentdialysate.

If a glucose-free dialysate is used, then glucose in the blood willrepresent the only source of glucose entering the effluent dialysate.The fluorescence resulting from displacement by glucose molecules couldbe detected by a non-invasive downstream fluorometer and compared to theactual clearance of citrate and calcium as measured by independentmeans. If there is a high degree of correlation, then the fluorometerreading can be translated into calcium and citrate clearance values.These values could then be used in a feedback loop to set the infusionrate of calcium into the venous blood such that the ionized calciumconcentration of the returning blood is at or near the desired value.

In some embodiments a method is provided for providing regional citrateanticoagulation when a selective cytopheretic device (SCD) is employedin the extracorporeal circuit, as depicted in FIGS. 3 and 4. A conundrumin the provision of citrate anticoagulation to extracorporeal therapiesoccurs where there is no need for diffusive or convective removal ofimpurities from the blood (and hence no dialysate) but rather thetherapeutic effect is achieved by simply bringing blood into contactwith beads or membranes incorporated within the blood treatment device.In these cases, there is no mechanism for extracting citrate from theblood and, as such, typical citrate anticoagulation would not befeasible. Four examples of such devices are the Cytosorb® manufacturedby Cytosorbents Corporation, the Hemopurifier manufactured by AethlonMedical Inc., the SCD developed by Cytopherx, Inc. of Ann Arbor Mich.and the Toraymyxin column distributed by Spectral Diagnostics, Inc.

The case of the Selective Cytopheretic Device (SCD) is of specialinterest given that its clinical efficacy is dependent on a low ionizedcalcium environment. The intended use of this device is for treating avariety of inflammation-mediated disease states including sepsis andacute kidney injury. The device is a conventional hollow fiberhemofilter but one where the inner lumens of the hollow fibers are notintended to be perfused but rather whole blood is perfused on theoutside of the fibers where dialysate is normally circulated. Thecompany has determined that leukocytes can be largely deactivated byincurring a residence time in the spongy architecture of the outer wallsof these fibers, which contributes to an amelioration of the progressionof inflammation. However, this deactivation only occurs in a low ionizedcalcium environment such as that created by RCA.

As such, in some embodiments is a method of using RCA with this devicebut without requiring the use of large and costly amounts of dialysatewhose only purpose when using this device in cases not requiring renalreplacement therapy would be to clear citrate so as to avoid itsaccumulation in the patient. One approach would be to provide amechanism for extracting the large majority of calcium/citrate complexesformed by the infusion of citrate followed by separating the calciumfrom the citrate, sequestering the citrate from returning to the bloodwhile reinfusing the calcium previously removed back into the venousblood returning to the patient.

In some embodiments is provided a method for delivering regional citrateanticoagulation including an anion exchange cartridge located in a loopof recirculating dialysate that perfuses the inner lumens of the hollowfiber bundle of the SCD and the outer lumens of the hollow fibers of thehemofilter located downstream of the SCD. If the appropriate anionexchange resin is employed (e.g. AMBERLITE™ FPA90Cl, AMBERLITE™ FPA98Cl,or AMBERLITE™ FPA40Cl), the calcium citrate entering the recirculatingdialysate from the blood by diffusion (which can be maximized by runningthe dialysate flow rate at least twice the blood flow rate) will bebound by the anion exchange resin in exchange for chloride ions and thecalcium bound to the citrate will be liberated into the dialysate. Asthe dialysate is then circulated through a hemofilter or dialyzerdownstream of the SCD and near the connection to the patient's bloodaccess device, the same calcium previously extracted from the arterialblood line can be returned to the venous line via diffusion through thehemofilter/dialyzer while the SCD and hemofilter/dialyzer remainanticoagulated.

If the process is 100% efficient or nearly so, then no exogenousinfusion of calcium will be necessary and no sensors aimed atquantifying the extraction of citrate and calcium will be necessary. Ifthe process is not sufficiently efficient, then sensors, such as thosedescribed above, can be implemented with the aforementioned feedbackloop to control the rate of calcium infusion but with significantreductions in the amount of dialysate and calcium infusate required.

This same approach could be used when the SCD is used in conjunctionwith renal replacement therapy by, instead of recirculating dialysate inand out of the same reservoir, delivering it in a single pass manner asis conventionally done.

In some embodiments a method is provided for delivering regional citrateanticoagulation, wherein the method comprises introducing blood into anextracorporeal system comprising a hemofilter, infusing the blood withcitrate to form complexes of citrate-calcium, flowing the blood throughthe hemofilter, flowing dialysate over an anion exchange cartridge toliberate chloride in exchange for the citrate anions, thereby liberatingcalcium ions previously complexed with the citrate anions, flowing thedialysate that passed through the anion exchange cartridge through thehemofilter in a flow direction opposite of the blood flow, and returningthe blood that passed through the hemofilter to the subject. In someembodiments, the anion exchange cartridge comprises an anion exchangeresin selected from the group consisting of AMBERLITE™ FPA90Cl,AMBERLITE™ FPA98Cl, and AMBERLIIE™ FPA40Cl. In some embodiments, thesubject is undergoing continuous renal replacement therapy orintermittent dialysis. In some embodiments, the capture and infusion ofcalcium is accomplished in a dialysate single pass format or in adialysate recirculation format. In some embodiments, the dialysate flowrate is at least twice that of the blood flow rate.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it will be understood by those of skill in the art thatnumerous and various modifications can be made without departing fromthe spirit of the present disclosure. Therefore, it should be clearlyunderstood that the forms disclosed herein are illustrative only and arenot intended to limit the scope of the present disclosure, but rather toalso cover all modification and alternatives coming with the true scopeand spirit of the invention.

1. A method for delivering regional citrate anticoagulation to asubject, comprising: introducing blood into an extracorporeal systemcomprising a hemofilter; infusing the blood with citrate to formcomplexes of citrate/calcium; flowing the blood through the hemofilter;flowing dialysate through the hemofilter in a flow direction opposite ofthe blood flow; measuring the conductivity of the dialysate prior topassage through the hemofilter and measuring the conductivity of thedialysate after passage through the hemofilter to determine adifferential conductivity; determining an actual clearance of calciumand of citrate through the membrane; correlating the differentialconductivity to the actual clearance of calcium and citrate; infusingblood that has passed through the hemofilter with calcium chloride basedon the measured differential conductivity; and returning the blood tothe subject.
 2. The method of claim 1, wherein the dialysate flow rateis at least twice that of the blood flow rate.
 3. The method of claim 2,wherein the dialysate flow rate is 400 mL/min.
 4. The method of claim 1,wherein the subject is undergoing continuous renal replacement therapyor intermittent dialysis.
 5. The method of claim 1, wherein the captureand infusion of calcium is accomplished in a dialysate single passformat or in a dialysate recirculation format.
 6. A method fordelivering regional citrate anticoagulation to a subject, comprising:introducing blood into an extracorporeal system comprising a hemofilterand an effluent dialysate flow path having a glucose exchange mediumlocated therein, and wherein the glucose exchange medium comprises alectin attached thereto, and is saturated with fluorescently-labeleddextran; infusing the blood with citrate to form complexes ofcitrate/calcium; flowing the blood through the hemofilter; flowingdialysate through the hemofilter in a flow direction opposite of theblood flow; flowing the dialysate that passed through the hemofilterthrough the glucose exchange medium, thereby displacing thefluorescently-labeled dextran; detecting the displaced fluorescentlylabeled dextran to determine the concentration of glucose in theeffluent dialysate flow path; infusing the blood that passed through thehemofilter with calcium chloride based on the measured concentration ofglucose; and returning the blood to the subject.
 7. The method of claim6, wherein the porous membrane comprises one or more of the lectinsConcanavalin A, Galanthus nivalis lectin (GNA), Lens culinaris (LCH),Ricinus communis Agglutinin (RCA), Arachis hypogaea (PNA), Artocarpusintegrifolia (AIL), Vicia villosa (VVL), Triticum vulgaris (WGA),Sambucus nigra (SNA), Maackia amurensis (MAL), Maackia amurensis (MAH),Ulex europaeus (UEH), or Aleuria aurantia (AAL), preferably at leastConcanavalin A.
 8. The method of claim 6, wherein the fluorescentlylabeled dextran is labeled with fluorescein isothiocyanate (FITC). 9.The method of claim 6, wherein the glucose exchange medium is selectedfrom the group consisting of a cartridge, a column, a resin, a bead, ora porous membrane.
 10. The method of claim 6, wherein the dialysate flowrate is at least twice that of the blood flow rate.
 11. The method ofclaim 6, wherein the subject is undergoing continuous renal replacementtherapy or intermittent dialysis.
 12. The method of claim 6, wherein thecapture and infusion of calcium is accomplished in a dialysate singlepass format or in a dialysate recirculation format.
 13. A method forproviding regional citrate anticoagulation to a subject, the methodcomprising: introducing blood into an extracorporeal system comprising aselective cytopheretic device (SCD) and a hemofilter; infusing the bloodwith citrate, wherein the citrate binds to calcium in the blood formingcomplexes of calcium/citrate; flowing dialysate over an anion exchangecartridge to liberate chloride in exchange for the citrate anions,thereby liberating calcium ions previously complexed with citrate; andinfusing the blood that passed through the hemofilter with calciumchloride; and returning the blood to the subject.
 14. The method ofclaim 13, wherein the dialysate containing the calcium chlorideliberated from the anion exchange resin is passed through the hemofilterin a direction opposite to that of the blood such that the calciumchloride diffuses into the blood and returns to the subject.
 15. Themethod of claim 13, wherein the anion exchange cartridge comprises ananion exchange resin selected from the group consisting of AMBERLITE™FPA90Cl, AMBERLITE™ FPA98Cl, and AMBERLITE™ FPA40Cl.
 16. The method ofclaim 13, wherein the extracorporeal system further comprises one ormore sensors for measuring the conductivity of the dialysate fordetermination of the amount of calcium chloride to infuse into theblood.
 17. The method of claim 13, wherein the subject is undergoingcontinuous renal replacement therapy or intermittent dialysis.
 18. Themethod of claim 13, wherein the capture and infusion of calcium isaccomplished in a dialysate single pass format or in a dialysatecirculation format.
 19. A method for delivering regional citrateanticoagulation to a subject, comprising: introducing blood into anextracorporeal system comprising a hemofilter; infusing the blood withcitrate to form complexes of citrate-calcium; flowing the blood throughthe hemofilter; flowing dialysate over an anion exchange cartridge toliberate chloride in exchange for the citrate anions, thereby liberatingcalcium ions previously complexed with the citrate anions; flowing thedialysate that passed through the anion exchange cartridge through thehemofilter in a flow direction opposite of the blood flow; and returningthe blood that passed through the hemofilter to the subject.
 20. Themethod of claim 19, wherein the anion exchange cartridge comprises ananion exchange resin selected from the group consisting of AMBERLITE™FPA90Cl, AMBERLITE™ FPA98Cl, and AMBERLITE™ FPA40Cl.
 21. The method ofclaim 19 or 20, wherein the subject is undergoing continuous renalreplacement therapy or intermittent dialysis.
 22. The method of claim19, wherein the capture and infusion of calcium is accomplished in adialysate single pass format or in a dialysate recirculation format. 23.The method of claim 19, wherein the dialysate flow rate is at leasttwice that of the blood flow rate.